EXCITOTOXICITY AND NEUROPROTECTION

Glutamate, the most widely used excitatory amino acid transmitter in t he brain, stimulates ionotropic and metabotropic receptors. There is a n increased release of glutamate after cerebral ischemia or hypoxia wh ich could cause overstimulation of its receptors leading to an increas e in the intracellular Ca2+ concentration ([Ca2+](i)). Sustained eleva tion in [Ca2+](i) is assumed to set various pathological processes int o motion which could degenerate neurons by activating proteases, lipas es, endonucleases and nitric oxide synthases and by promoting the form ation of free oxygen radicals. Drugs capable of inhibiting the increas e in [Ca2+](i) such as calcium antagonists, NMDA and AMPA antagonists protect neurons against damage. To prevent Ca2+ influx into neurons mo st efficaciously NMDA-operated and voltage-sensitive Ca2+ channels wer e simultaneously blocked. Both the NMDA antagonist dizocilpine (MK-801 ) and the calcium antagonist nimodipine were added to glutamate-treate d cultures of rat hippocampal neurons and these two drugs caused an ov eradditive neuroprotective effect. NMDA receptor stimulation leads to an augmented formation of NO and free oxygen radicals and that is the reason why radical scavengers are effective in protecting neurons agai nst glutamate-induced damage. Furthermore, TGF-beta 1, the lesion form of the TGF-beta family which is discussed to stabilize the cellular C a2+ homeostasis and to reduce free radical formation also protects neu rons against excitotoxic damage. It is suggested that an increased [Ca 2+](i) is significantly involved in neuronal damage and the inhibition of the increase in [Ca2+](i) protects neurons against damage.